CHICAGO — The long-acting injectable cabotegravir (ViiV Healthcare), a novel HIV prevention therapy, can persist in the body for more than a year in some people, surprising new data from the phase 2a ÉCLAIR study show.
"It's an important finding because you need to give patients some sense of when that protection ends," said Jeanne Marrazzo, MD, from the University of Alabama at Birmingham.
"These data suggest that not only is that time of protection variable among people, you actually have a fair number of people who have drug present for a really long time," Dr Marrazzo told Medscape Medical News. What this means for these patients is not yet understood.
For now, the researchers will return to their labs and their subjects to try to correlate the drug's "tail" — that is, how long the drug concentrates in the blood after it's discontinued — with biomarkers that can predict how long it persists in the body.
The ÉCLAIR data were presented here at HIV Research for Prevention 2016.
In the pre-exposure prophylaxis (PrEP) trial, 127 men without HIV who were at low risk for the virus were randomized to receive cabotegravir or placebo. After 4 weeks of oral formulations to check for adverse effects and toxicity, injections of cabotegravir 800 mg or saline were administered.
During the 41-week study period, the men received three shots of the long-acting drug in the buttocks. Follow-up ran until week 81.
Understanding the Slow Absorbers
The mean half-life of the drug was 18 days after the first injection; this rose to 40 days after the third injection. However, the overall data were less consistent.
In some men, cabotegravir dropped below effective levels 24 weeks after injection. In others, cabotegravir was still detectable in the blood 52 weeks after injection.
Those amounts are consistent with a drug that persists for "several additional months," said Susan Ford, PhD, a pharmacokineticist at Parexel in Deerfield, Illinois, who has been working on the drug for close to a decade.
Body mass index tended to be higher in these so-called slow absorbers than in fast absorbers, she explained, but it is not possible to know at this point whether BMI is a deciding factor in absorption rates.
Because all the study participants are at low risk for HIV, "we don't expect any infections" in these cohorts, Dr Ford told Medscape Medical News. "So when the tail is prolonged — if it's prolonged — the risk of infection is low and the risk of developing a resistant strain is low. It's a really good place to look at this question."
A "Double Surprise"
This is the second time unexpected findings from the ÉCLAIR study have been unveiled, which Dr Ford referred to as "a double surprise."
Researchers previously found that drug concentration levels were peaking higher and dropping lower — below protective levels, in some cases — than preclinical models had projected, as reported by Medscape Medical News. This led to a change in the dosing interval from every 12 weeks to every 8 weeks.
She said researchers will use these data to inform another study on the same medication — HIV Prevention Trials Network (HPTN) 077 — which will include a large number of women.
Injectable Cabotegravir in the Real World
At least some members of the standing-room-only crowd were left wanting to know more.
These findings raise "really fascinating questions," said Dr Marrazzo, who is cochair of the conference. Is there a way to predict who will have this long tail? Does the toxicity of cabotegravir change in relation to the time it persists in the body? How will doctors manage patients in clinical practice who are coming off cabotegravir and using the combination of tenofovir and emtricitabine (Truvada, Gilead) to manage the tail?
And then there is the big question, she said: "Could the subtherapeutic levels provoke resistance in the virus?"
"That happens with acute infection with tenofovir," she pointed out, and "would be a bit concerning."
But this does not mean that injectable cabotegravir is fatally flawed.
"I don't think it's a nonstarter," said Dr Marrazzo. "It just means there's a subgroup that will be looked at carefully" and that there are a lot of scientifically exciting answers yet to come.
Dr Ford is an employee of Parexel International. Dr Smith is an employee of Viiv Healthcare. Dr Marrazzo and Dr Hillier have disclosed no relevant financial relationships.
HIV Research for Prevention Conference: Abstract OA12.06LB. Presented October 19, 2016.
Medscape Medical News © 2016 WebMD, LLC
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Cite this: More Surprises From ÉCLAIR: Cabotegravir's 'Long Tail' - Medscape - Oct 24, 2016.